Submissions for variant NM_001317778.2(SFTPC):c.445G>C (p.Ala149Pro)

gnomAD frequency: 0.00012  dbSNP: rs202145169

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000391181	SCV000473021	likely benign	Interstitial lung disease 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000305466	SCV000473022	likely benign	Surfactant metabolism dysfunction, pulmonary, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358404	SCV002108541	uncertain significance	not provided	2022-08-27	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 362560). This missense change has been observed in individual(s) with clinical features of SFTPC-related conditions (PMID: 25782673). This variant is present in population databases (rs202145169, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 155 of the SFTPC protein (p.Ala155Pro).
Mendelics	RCV002248630	SCV002520007	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358404	SCV001554124	likely benign	not provided		no assertion criteria provided	clinical testing	The SFTPC p.Ala149Pro variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs202145169), LOVD 3.0 and in ClinVar (classified as likely benign by Illumina for Idiopathic fibrosing alveolitis, chronic form and Pulmonary Surfactant Metabolism Dysfunction, Dominant). The variant was also identified in control databases in 58 of 279270 chromosomes at a frequency of 0.000208 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 13 of 30600 chromosomes (freq: 0.000425), European (non-Finnish) in 41 of 127120 chromosomes (freq: 0.000323), Other in 1 of 7130 chromosomes (freq: 0.00014), Latino in 2 of 35364 chromosomes (freq: 0.000057) and African in 1 of 24166 chromosomes (freq: 0.000041); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Ala149 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.